As of 1984, heart failure has been estimated to occur in 2 million patients in the United States alone with approximately 250,000 new cases and 200,000 deaths each year. These numbers have steadily increased with increasing life expectancy and expansion of the higher risk geriatric population. Despite the advent of more effective therapy, most, if not all patients, continue to succumb to this disease. Ischemic heart disease is by far the most common etiology leading to heart failure. Significant loss of viable left ventricular (LV) myocardium occurs after a large infarction or multiple smaller infarctions and results in considerable LV dysfunction. It is now recognized that during the transition period between a state of compensated LV dysfunction and cardiac decompensation and overt heart failure, lV function continues to deteriorate despite the absence of any additional concurrent clinical events. The factors responsible for this progressive worsening of LV function are not know. The present proposal tests the hypothesis that the progressive deterioration of LV function, during this transition period, results from progressive loss of functional cardiac units mediated by ongoing degeneration and necrosis of residual viable cardiomyocytes. The proposed studies are also designed to test the hypothesis that the hypothesis that the progressive degeneration and loss of residual viable cadiomyocytes result from the development of reactive interstitial fibrosis which acts as a barrier to oxygen diffusion between capillaries and the collagen encircled cardiomyocytes. Finally, studies are proposed to test the hypothesis that angiotensin converting enzyme inhibitors prevent or retard the progressive deterioration of LV function by preventing or attenuating the development of interstitial fibrosis. These interrelated hypotheses will be tested in a canine model of chronic heart failure produced by multiple sequential intracoronary microembolizations. This canine preparation manifests spontaneous deterioration of lV function and reactive interstitial fibrosis long-after cessation of coronary microembolizations and, therefore, is ideally suited for detailed interrogation of the proposed hypotheses. Uncovering the mechanism(s) responsible for the transition from compensated to decompensated heart failure is essential in the development of effective and target specific therapies aimed at preventing or, at the very least, retarding the progression toward overt heart failure.